Mechanisms of commensal bacteria induced humoral immunity

项目摘要/摘要 微生物群影响人类健康的许多方面，并与疾病有关，如 肥胖、炎症性肠病、糖尿病和过敏。寄主与共生之间的平衡 细菌在大多数健康的人身上都保存得很好。对肠道有贡献的一个宿主因素 动态平衡是IgA亚类的抗体。产生IgA的浆细胞在黏膜组织中被发现 作为肠道的固有层，但也可以在包括骨髓在内的全身部位发现。 然而，只有在某些细菌存在的情况下，才能发现高水平的骨髓免疫球蛋白A。 骨髓中分泌IgA的浆细胞频率的增加与浓度的增加有关 在多菌传播的脓毒症模型中，已被证明具有保护作用的血清IgA。这个 细菌诱导全身性IgA反应的机制尚不清楚。这项提议的主要目标是 采取公正的方法来定义共生细菌用来诱导 全身免疫球蛋白A。此外，我们将研究物种间的相互作用如何有助于系统的IgA特异性。 总之，这项建议将提供一个框架，以了解系统性抗体反应是如何 对共生细菌的反应而诱导的。这一理解可能会导致旨在 维持肠道内环境稳定或使用共生细菌作为疫苗输送系统。这项建议 将支持我们研究计划的总体愿景，以了解 细菌和宿主通过破译细菌所用的基因水平的机制来诱导IgA反应。

Project Summary/Abstract The microbiome affects many aspects of human health and has been linked to diseases such as obesity, inflammatory bowel disease, diabetes, and allergy. The balance between host and commensal bacteria is well maintained in most healthy individuals. One host factor that contributes to intestinal homeostasis is antibody of the IgA subclass. Plasma cells that produce IgA are found in mucosal tissues such as the lamina propria of the gut, but they can also be found in systemic sites including the bone marrow. However, high levels of bone marrow IgA are only found in the presence of certain consortia of bacteria. Increased frequencies of bone marrow IgA-secreting plasma cells are associated with increased concentration of serum IgA that has been shown to be protective in a sepsis model of polymicrobial dissemination. The mechanisms by which bacteria induce systemic IgA responses are unknown. The main goal of this proposal is to take an unbiased approach to defining gene-level mechanisms used by commensal bacteria to induce systemic IgA. Additionally, we will examine how inter-species interactions contribute to systemic IgA specificity. Together, this proposal will provide a framework for understanding how systemic antibody responses are induced in response to commensal bacteria. This understanding could lead to novel therapies aimed at maintaining intestinal homeostasis or using commensal bacteria as a vaccine delivery system. This proposal will support the overall vision of our research program to understand the complex interplay at the interface of bacteria and host by deciphering gene-level mechanisms used by bacteria to induce IgA responses.